ABSTRACT: Nicotinic acetylcholine receptors (nAChRs) are pentameric channels expressed by neuronal and non-neuronal cells that are capable of signal transduction. Although much of what is known about the function of nAChRs relates to the nervous system, information about their roles in non-neuronal systems is rapidly emerging. nAChRs are expressed in lung and interesting work performed in non-human primates suggests that nAChR activation by nicotine leads to pulmonary structural/functional abnormalities. We explored the mechanisms by which nAChR activation leads to matrix expression and found that this effect is mediated through a specific subgroup of nAChRs termed 17 nAChRs. Upon activation of these receptors in lung fibroblasts, we observed induction of the MEK-1/Erk pathway and phosphorylation of the transcription factor CREB. In turn, CREB stimulated the expression of fibronectin, a matrix glycoprotein implicated in lung injury and repair. These events were blocked by 17 nAChR antagonists and were not present in 17 nAChR KO primary lung fibroblasts. In addition, we found that nAChR activation stimulates lung fibroblast proliferation through MEK-1/Erk-dependent pathways. Similar observations were made in mice chronically stimulated with nicotine, but not in developing and adult 17 nAChR KO animals. More recently, we documented an increase in the proliferation and expression of fibronectin in fibroblasts exposed to cigarette smoke extract, and observed an increase in fibronectin protein deposition in the lungs of mice exposed to tobacco smoke confirming the relevance of this process to tobacco-related disease. We also found that lung repair mechanisms appeared to be impaired after bleomycin-induced lung injury in the setting of chronic exposure to nicotine. These data unveil a novel role for non-neuronal nAChRs in control of lung tissue remodeling. Based on the above, we hypothesize that 17 nAChR activation in lung promotes tissue remodeling by stimulating the proliferation of fibroblasts and their overexpression of matrix components like fibronectin through MEK-1/Erk-dependent signals. At baseline, this leads to subtle alterations in matrix composition without causing overt consequences such as fibrosis. In contrast, in the setting of lung injury, this leads to exaggerated tissue remodeling that promotes inefficient repair and fibrosis. This will be tested in specific aims designed to: 1) Examine the role of 17 nAChRs in the proliferation, myofibroblast transdifferentiation, and matrix expression of lung fibroblasts, and the role of MEK-1/Erk in mediating these events in wildtype vs. 17 nAChR KO lung fibroblasts, 2) Examine the role of 17 nAChRs in lung injury and repair using wildtype and 17 nAChR KO mice in two models of lung injury (bleomycin model and the model of heterologous tracheal transplantation), and 3) Examine the effect of persistent 17 nAChR activation in lung repair after injury.